Theranostic Frontiers in HER2-Positive Breast Cancer: Nanomedicine Meets Morphology

Abstract HER2-positive breast cancer (∼15–20% of cases) represents a paradigm for targeted therapy, yet durable responses are limited by intrinsic and acquired resistance. Beyond molecular alterations, increasing evidence indicates that therapeutic failure emerges as a spatial and structural process. Constraints across scales, including CSC fractions (∼1–10%), limited antibody penetration (∼20–100 μm from functional vessels), and ADC processing kinetics over hours to days, generate heterogeneous drug exposure and response. Here, we review how nanomedicine-based theranostics intersects with morphological determinants of response in HER2-positive disease. We focus on four structure-linked axes: (i) CSC niches and spatial gradients, (ii) HER2 glycosylation and surface shielding, (iii) tunneling nanotubes as stress-induced conduits, and (iv) extracellular vesicles as signaling mediators and therapeutic decoys. We contextualize these mechanisms within current nanomedicine strategies, from antibody–drug conjugates to emerging nanoparticle platforms, highlighting how delivery, intracellular trafficking, and payload release are constrained by tumor architecture. Finally, we propose a morphology-driven nanotheranostics framework, in which nanoscale design is guided and validated by multiscale imaging, positioning morphology as a functional parameter to overcome resistance and improve spatially resolved HER2-targeted therapies.